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Poly(ethylene glycol)-peptide- and glycosaminoglycan-peptide conjugates obtained by a regio-selective amino acid protection strategy are converted into cell-instructive hydrogel matrices capable of inducing morphogenesis in embedded human vascular endothelial cells and dorsal root ganglia.

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Heparin and four-armed, end-functionalized polyethylene glycol (starPEG) were recently combined in sets of covalently linked biohybrid hydrogel networks capable of directing various therapeutically relevant cell types. To extend the variability and applicability of this novel biomaterials platform, the influence of size and molar ratio of the two building blocks on the hydrogel properties was investigated in the present study. Heparin and starPEG were converted in various molar ratios and in different molecular weights to tune swelling, stiffness and pore size of the obtained polymer networks. Hydrogels with a range of elastic moduli could be generated by controlling either the crosslinking density or the chain length of the starPEG, whereas altering the molecular mass of heparin did not significantly affect hydrogel strength. The concentration of heparin in the swollen gels was found to be nearly invariant at varying crosslinking degrees for any given set of building blocks but adjustable by the size of the building blocks. Since heparin is the base for all biofunctionalization schemes of the gels these findings lay the ground for an even more versatile customization of this powerful new class of biomaterials. OPEN ACCESSPolymers 2011, 3 603

research has revealed that, together with the provision of morphogens and the presentation of adhesion ligands, [ 2 ] the mechanical characteristics of extracellular matrices have a decisive infl uence on cell fate, provoking the development of materials with effective physical properties. [ 3 ] This interplay of biomolecular and biophysical signals thus defi nes an obvious, but until now unmet, need for a new generation of biomaterials that can be selectively and independently tuned for biomolecular properties and physical material parameters. A conceptual basis to address this need is currently missing. As such, we have developed a rational design approach relying on mean fi eld concepts to guide the design of biofunctional matrices. Considering the decisive role of electrostatic interactions in functional assemblies of living matter we selected a system that allows for a far-reaching modulation of structure-determining forces: crosslinking a hydrophilic and fl exible, multi-armed polymer (with four-armed, amino-terminated poly(ethylene glycol) (starPEG) as an example system known for its anti-adhesive characteristics towards proteins, [ 4 ] with a multifunctional, highly charged crosslinker (such as heparin (HEP) or a similarly charged glycosaminoglycan), which can function as a multivalent binding site capable of complexing a plethora of important bioactive molecules. [ 5 ] We explored whether and how the combination of the particular gel components permits varying the physical and biomolecular characteristics of the swollen materials independently.Based on the successful experimental verifi cation of the theoretical predictions and the functionalization of starPEG-heparin gels with adhesive ligand peptides (such as the integrinbinding arginine-glycine-aspartic acid sequence (RGD))) and morphogens (vascular endothelial growth factor (VEGF), bone morphogenetic protein-2 (BMP-2)) through covalent and noncovalent conjugation schemes we were able to illustrate the resulting options for two selected example systems: studying the interplay of matrix elasticity and growth factor presentation in inducing the pro-angiogenic state of human endothelial cells and promoting osteogenic differentiation of human mesenchymal stem cells we identifi ed effective combinations of matrix parameters and demonstrated exciting options for the fully matrix controlled direction of the cells, i.e., removed the Using Mean Field Theory to Guide Biofunctional Materials DesignCell-instructive characteristics of extracellular matrices (ECM) resulting from a subtle balance of biomolecular and biophysical signals must be recapitulated in engineered biomaterials to facilitate regenerative therapies. However, no material explored so far allows the independent tuning of the involved molecular and physical cues due to the inherent correlation between biopolymer concentration and material properties. Addressing the resulting challenge, a rational design strategy for ECM-inspired biohybrid hydrogels based on multi-armed poly(ethylene glycol) and he...